Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to be Δ9-tetrahydrocannabinol (Δ9-THC). Detailed research has revealed that the biological action of Δ9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CB1 and CB2. The CB1 receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2-arachidonoyl glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to Δ9-THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.
Excessive exposure to Δ9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation. Specific synthetic ligands for the cannabinoid receptors have been developed and have aided in the characterization of the cannabinoid receptors: CP55,940 (J. Pharmacol. Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther. 1993, 264, 1352-1363); SR141716A (FEBS Lett. 1994, 350, 240-244; Life Sci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999, 288, 582-589). The pharmacology and therapeutic potential for cannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents 1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press, NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538; Trends in Pharma. Sci. 2000, 21, 218-224). There is at least one CB1 modulator characterized as an inverse agonist or an antagonist, N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A), in clinical trials for treatment of eating disorders.
Hitherto, several classes of CB1 modulators are known. U.S. Pat. Nos. 5,624,941 and 6,028,084, PCT Publication Nos. WO98/43636 and WO98/43635, and European Patent Application No. EP-658546 disclose substituted pyrazoles having activity against the cannabinoid receptors. PCT Publication Nos. WO98/31227 and WO98/41519 also disclose substituted pyrazoles having activity against the cannabinoid receptors. PCT Publication Nos. WO98/37061, WO00/10967, and WO00/10968 disclose diaryl ether sulfonamides having activity against the cannabinoid receptors. PCT Publication Nos. WO97/29079 and WO99/02499 disclose alkoxy-isoindolones and alkoxy-quinolones as having activity against the cannabinoid receptors. U.S. Pat. No. 5,532,237 discloses N-benzoyl-indole derivatives having activity against the cannabinoid receptors. U.S. Pat. No. 4,973,587, U.S. Pat. No. 5,013,837, U.S. Pat. No. 5,081,122, U.S. Pat. No. 5,112,820, and U.S. Pat. No. 5,292,736 disclose aminoalkylindole derivatives as having activity against the cannabinoid receptors. PCT Publication No. WO03/027076 discloses 1H-imidazole derivatives having CB1 agonist, CB1 partial agonist or CB1 antagonist activity. PCT Publication No. WO03/026648 discloses 4,5-dihydro-1H-pyrazole derivatives having potent CB1-antagonist activity. US Publication No. US 2003/0114495 discloses substituted imidazoles as cannabinoid receptor modulators. US Publication No. US 2003/0119810 discloses pharmaceutical compositions containing 3-aminoazetidine derivatives possessing a high affinity for CB1 receptors.
[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone RN 439128-75-3, [4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone RN394228-83-2, and [4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone RN 394228-85-4 are found in the CA database.
There still remains a need for potent low molecular weight CB1 modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.